Mucosal melanoma - a couple of reports

Melanoma sucks.  Mucosal melanoma sucks even more.  Here are some prior posts:

Mucosal melanoma - abstracts from 2016 to now

Here is an abstract regarding the use of pembro and a case report in which a topical anti-fungal was used in a patient with vaginal melanoma (although radiation to a brain met and nivo was started as well....so it's a bit muddy!!!) to good effect.  For what they're worth:

Antitumour activity of pembrolizumab in advanced mucosal melanoma: a post-hoc analysis of KEYNOTE-001, 002, 006. Hamid, Robert, Ribas, Hodi, et al.Br J Cancer. 2018 Sep 11.

Mucosal melanoma is an aggressive melanoma with poor prognosis. We assessed efficacy of pembrolizumab in patients with advanced mucosal melanoma in KEYNOTE-001 (NCT01295827), -002 (NCT01704287), and -006 (NCT01866319).

Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) or 10 mg/kg Q2W or Q3W. Response was assessed by independent central review per RECIST v1.1.

1567 patients were treated and 84 (5%) had mucosal melanoma. Fifty-one of 84 were ipilimumab-naive. In patients with mucosal melanoma, the objective response rate (ORR) was 19% (11-29%), with median duration of response (DOR) of 27.6 months (range 1.1 + to 27.6). Median progression-free survival (PFS) was 2.8 months (2.7-2.8), with median overall survival (OS) of 11.3 months (7.7-16.6). ORR was 22% (11-35%) and 15% (5-32%) in ipilimumab-naive and ipilimumab-treated patients.

Pembrolizumab provides durable antitumour activity in patients with advanced mucosal melanoma regardless of prior ipilimumab.

Itraconazole treatment of primary malignant melanoma of the vagina evaluated using positron emission tomography and tissue cDNA microarray: a case report.  Inoew, Tsubamoto, Isono-Nakata, et al.  BMC Cancer. 2018 Jun 4.

Primary malignant melanoma of the vagina is extremely rare, with a poorer prognosis than cutaneous malignant melanoma. Previous studies have explored the repurposing of itraconazole, a common oral anti-fungal agent, for the treatment of various cancers. Here, we describe a patient with metastatic, unresectable vaginal malignant melanoma treated with 200 mg oral itraconazole twice a day in a clinical window-of-opportunity trial.

A 64-year-old Japanese woman with vaginal and inguinal tumours was referred to our institution. On the basis of an initial diagnosis of vaginal cancer metastatic to the inguinal lymph nodes, we treated her with itraconazole in a clinical trial until the biopsy and imaging study results were obtained. During this period, biopsies were performed three times, and ¹⁸F-fluoro-deoxyglucose positron emission tomography (FDG/PET)-computed tomography (CT) was performed twice. Biopsy results confirmed the diagnosis of primary malignant melanoma of the vagina. Imaging studies revealed metastases to multiple sites, including the brain, for which she underwent gamma-knife radiosurgery. During the window period before nivolumab initiation, the patient received itraconazole for 30 days. Within a week of itraconazole initiation, pain in the inguinal nodes was ameliorated. PET-CT on days 6 and 30 showed a reduction in tumour size and FDG uptake, respectively. The biopsied specimens obtained on days 1, 13, and 30 were subjected to cDNA microarray analysis, which revealed a 100-fold downregulation in the transcription of four genes: STATH, EEF1A2, TTR, and CDH2. After 12 weeks of nivolumab administration, she developed progressive disease and grade 3 immune-related hepatitis. Discontinuation of nivolumab resulted in the occurrence of left pelvic and inguinal pain. Following re-challenge with itraconazole, the patient has not reported any pain for 4 months.

The findings of this case suggest that itraconazole is a potential effective treatment option for primary malignant melanoma of the vagina. Moreover, we identified potential itraconazole target genes, which could help elucidate the mechanism underlying this disease and potentially aid in the development of new therapeutic agents.

Wishing you all my best. - c

CheckMate 067 - 4 year outcomes for nivo/ipi combo vs nivo alone in melanoma patients

I have been following the data (and contributing to some) around immunotherapy for over 8 years!  So of course I've followed the CheckMate 067 trial.  Here are just a few early reports:   CheckMate 067 - ipi/nivo combo

Now, this ~

Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Hodi, Chiarion-Sileni, Gonzalez, et al. Lancet Oncol. 2018 Oct 18.  

Previously reported results from the phase 3 CheckMate 067 trial showed a significant improvement in objective responses, progression-free survival, and overall survival with nivolumab plus ipilimumab or nivolumab alone compared with ipilimumab alone in patients with advanced melanoma. The aim of this report is to provide 4-year updated efficacy and safety data from this study.  

In this phase 3 trial, eligible patients were ... previously untreated, unresectable, stage III or stage IV melanoma, known BRAF^V600 mutation status, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 1:1:1 to receive intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg every 2 weeks plus placebo, or ipilimumab 3 mg/kg every 3 weeks for four doses plus placebo. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by PD-L1 status, BRAF mutation status, and metastasis stage. The patients, investigators, study site staff, and study funder were masked to the study drug administered. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all patients who received at least one dose of study drug. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of May 10, 2018. This study is registered with ClinicalTrials.gov, number NCT01844505.  

Between July 3, 2013, and March 31, 2014, 945 patients were enrolled and randomly assigned to nivolumab plus ipilimumab (n=314), nivolumab (n=316), or ipilimumab (n=315). Median follow-up was 46·9 months (IQR 10·9-51·8) in the nivolumab plus ipilimumab group, 36·0 months (10·5-51·4) in the nivolumab group, and 18·6 months (7·6-49·5) in the ipilimumab group. At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (38·2-not reached) in the nivolumab plus ipilimumab group, 36·9 months (28·3-not reached) in the nivolumab group, and 19·9 months (16·9-24·6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0·54 and for nivolumab versus ipilimumab was 0·65. Median progression-free survival was 11·5 months (95% CI 8·7-19·3) in the nivolumab plus ipilimumab group, 6·9 months (5·1-10·2) in the nivolumab group, and 2·9 months (2·8-3·2) in the ipilimumab group. The hazard ratio for progression-free survival for the combination versus ipilimumab was 0·42 and for nivolumab versus ipilimumab was 0·53. Treatment-related grade 3-4 adverse events were reported in 185 (59%) of 313 patients who received nivolumab plus ipilimumab, 70 (22%) of 313 who received nivolumab, and 86 (28%) of 311 who received ipilimumab. The most common treatment-related grade 3 adverse events were diarrhoea in the nivolumab plus ipilimumab group (29 [9%] of 313) and in the nivolumab group (nine [3%] of 313) and colitis in the ipilimumab group (23 [7%] of 311); the most common grade 4 adverse event in all three groups was increased lipase (15 [5%] of 313 in the combination group, ten [3%] of 313 in the nivolumab group, and four [1%] of 311 in the ipilimumab group). Serious adverse events were not analysed for the 4-year follow-up. In total for the study, there were four treatment-related deaths: two in the nivolumab plus ipilimumab group (one cardiomyopathy and one liver necrosis), one in the nivolumab group (neutropenia), and one in the ipilimumab group (colon perforation). No additional treatment-related deaths have occurred since the previous (3-year) analysis.

The results of this analysis at 4 years of follow-up show that a durable, sustained survival benefit can be achieved with first-line nivolumab plus ipilimumab or nivolumab alone in patients with advanced melanoma.

At this point, these results are not surprising.  The ipi/nivo group median overall survival was not reached at 38 months, not reached for nivo alone at 36 months, and was 19 months in the ipi only group.  Side effects greatest with 59% of patients experiencing them with ipi/nivo, experienced by 22% taking nivo alone, and by 28% on ipi as a single agent.  The most common grade 3 side effect was diarrhea/colitis.  The most common grade 4 side effects was increased lipase.

Thanks, ratties!!! May we all continue to beat our assigned expiration dates!!! - c

Important stuff floating in our blood - tumor DNA, micro RNA, cytokines - can determine tumor burden, predict response, and side effects for melanoma patients!!!

Continuing from yesterday.....  Our blood is a fairly accessible information rich soup that can tell us all sorts of things about our bodies!!!  One important ingredient for melanoma patients is circulating tumor DNA.  Here's a load of prior reports: Circulating tumor DNA - to determine diagnosis, disease burden, response to therapy, etc  Here are a couple more reports:

Correlation between circulating tumour DNA and metabolic tumour burden in metastatic melanoma patients.  McEvoy, Warburton, Al-Ogaili, et al. BMC Cancer. 2018 Jul 9.

Circulating tumour DNA (ctDNA) may serve as a measure of tumour burden and a useful tool for non-invasive monitoring of cancer. However, ctDNA is not always detectable in patients at time of diagnosis of metastatic disease. Therefore, there is a need to understand the correlation between ctDNA levels and the patients' overall metabolic tumour burden (MTB).  Thirty-two treatment naïve metastatic melanoma patients were included in the study. MTB and metabolic tumour volume (MTV) was measured by 18F-fluoro-D-glucose positron emission tomography/computed tomography (FDG PET/CT). Plasma ctDNA was quantified using droplet digital PCR (ddPCR).  CtDNA was detected in 23 of 32 patients. Overall, a significant correlation was observed between ctDNA levels and MTB. CtDNA was not detectable in patients with an MTB of greater than/= to 10, defining this value as the lower limit of tumour burden that can be detected through ctDNA analysis by ddPCR.  We showed that ctDNA levels measured by ddPCR correlate with MTB in treatment naïve metastatic melanoma patients and observed a limit in tumour size for which ctDNA cannot be detected in blood. Nevertheless, our findings support the use of ctDNA as a non-invasive complementary modality to functional imaging for monitoring tumour burden.

From validity to clinical utility: the influence of circulating tumor DNA on melanoma patient management in a real-world setting. Rose, Luber, Makell, et al. Mol Oncol. 2018 Aug 16.

Melanoma currently lacks a reliable blood-based biomarker of disease activity, although circulating tumor DNA (ctDNA) may fill this role. We investigated the clinical utility (i.e., impact on clinical outcomes and interpretation of radiographic data) of measuring ctDNA in patients with metastatic or high-risk resected melanoma. Patients were prospectively accrued into greater than/= to 1 of 3 cohorts, as follows. Cohort A: patients with radiographically-measurable metastatic melanoma who underwent comparison of ctDNA measured by a BEAMing digital PCR assay to tissue mutational status and total tumor burden; when appropriate, determinations about initiation of targeted therapy were based on ctDNA data. Cohorts B and C: patients with BRAF- or NRAS-mutant melanoma who had either undergone surgical resection of high-risk disease (cohort B) or were receiving or had received medical therapy for advanced disease (cohort C). Patients were followed longitudinally with serial ctDNA measurements with contemporaneous radiographic imaging to ascertain times to detection of disease activity and progressive disease, respectively. The sensitivity and specificity of the ctDNA assay was 86.8% and 100%, respectively. Higher tumor burden and visceral metastases were found to be associated with detectable ctDNA. In 2 patients in cohort A, ctDNA test results revealed a targetable mutation where tumor testing had not; both patients experienced a partial response to targeted therapy. In 4 of 30 patients with advanced melanoma, ctDNA assessments indicated evidence of melanoma activity that predicted radiographic evidence of disease progression by 8, 14, 25 and 38 weeks, respectively. CtDNA was detectable in 3 of these 4 patients coincident with radiographic evaluations that alone were interpreted as showing no evidence of neoplastic disease. Our findings provide evidence for the clinical utility of integrating ctDNA data in managing patients with melanoma in a real-world setting.

Among the many bio-markers present in our blood, there's also circulating RNA.   Prior reports:  RNA and biomarkers generally  Now, this:

Extracellular microvesicle microRNAs as predictive biomarkers for targeted therapy in metastastic cutaneous malignant melanoma.  Svedman, Loncharoenkal, Bottaj, et al. PLoS One. 2018 Nov.

Mitogen activated-protein kinase pathway inhibitors (MAPKis) improve treatment outcome in patients with disseminated BRAFV600 mutant cutaneous malignant melanoma (CMM) but responses are of limited duration due to emerging resistance. Although extensive research in mechanisms of resistance is being performed, predictive biomarkers for durable responses are still lacking. We used miRNA qPCR to investigate if different levels of extracellular microvesicle microRNA (EV miRNA) in matched plasma samples collected from patients with metastatic IV BRAFV600 mutated CMM before, during and after therapy with MAPKis could serve as predictive biomarkers.  EV miRNAs were extracted from plasma samples from 28 patients collected before and during therapy, measured by quantitative PCR-array and correlated to therapy outcome. Increased levels of EV let-7g-5p during treatment compared to before treatment were associated with better disease control with MAPKis. Elevated levels of EV miR-497-5p during therapy were associated with prolonged progression free survival (PFS).  EV miRNAs let-7g-5p and miR-497-5p were identified as putative novel predictive biomarkers of MAPKi treatment benefit in metastatic CMM patients highlighting the potential relevance of assessing EV miRNA during and after treatment to unravel novel mechanisms of resistance.

Circulating cytokines are substances like interleukin, interferon, and growth factors, that cells in our immune system secrete in order to affect other cells. Here's a report for a little background:  Eosinophilia with Nivo and Pembro - A predictor of success?!!
Here they are being examined as predictors of toxicity to immunotherapy:

Circulating cytokines predict immune-related toxicity in melanoma patients receiving anti-PD-1-based immunotherapy. Lim, Lee, Gide, et al. Clin Cancer Res. 2018 Nov 8.  

Combination PD-1 and CTLA-4 inhibitor therapy has dramatically improved the survival of patients with advanced melanoma but is also associated with significant immune-related toxicities. This study sought to identify circulating cytokine biomarkers of treatment response and immune-related toxicity.  The expression of 65 cytokines was profiled longitudinally in 98 melanoma patients treated with PD-1 inhibitors, alone or in combination with anti-CTLA-4, and in an independent validation cohort of 49 patients treated with combination anti-PD-1 and anti-CTLA-4. Cytokine expression was correlated with RECIST response and immune-related toxicity, defined as toxicity that warranted permanent discontinuation of treatment and administration of high dose steroids.

Eleven cytokines were significantly upregulated in patients with severe immune-related toxicities at baseline and early during treatment. The expression of these eleven cytokines was integrated into a single toxicity score, the CYTOX score, and the predictive utility of this score was confirmed in the discovery and validation cohorts. 

The CYTOX score is predictive of severe immune-related toxicity in melanoma patients treated with combination anti-CTLA-4 and anti-PD-1 immunotherapy. This score, which includes pro-inflammatory cytokines such as IL-1a, IL-2 and IFNa2, may help in the early management of severe, potentially life-threatening immune-related toxicity.

Hoping for much more consistency and use of these relatively simple tests in order to reap better treatment outcomes for melanoma patients in 2019!!! - c

Pretreatment NLR levels prognostic in melanoma patients!

As noted in the discussion of adjuvant treatment by melanoma Big Dogs, biomarkers will no doubt come to play an important role in diagnosis and treatment management for melanoma patients.  I've reported on simple, easy to attain and run blood values to provide prognostic and response information for melanoma patients for a looooong time.  Collection of blood for the measurement and comparison of the quantity of white blood cells is just one.  Here are lots of reports:  Prior reports on neutrophils

Now there's this:

Prognostic significance of pretreatment neutrophil-to-lymphocyte ratio in melanoma patients:  A meta-analysis.  Zhan, Ma, Jian.  Clin Chim Acta. 2018 May 20.

Recently, the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) has been widely evaluated in many cancers. Here we assessed the prognostic value of pretreatment NLR in melanoma.  A range of online databases was systematically searched up to March, 2018 for identify available studies which assessed the prognostic significance of NLR. Data from studies reporting a hazard ratio (HR) and 95% confidence interval (CI) were weighted by generic inverse-variance and pooled in random effects meta-analysis.

Twelve studies with 4593 individuals were included. Patients with elevated NLR had a significantly shorter overall survival (OS) and disease-free survival (DFS)/progression-free survival (PFS). Subgroup analyses showed that the negative prognostic effect of elevated NLR on OS remained substantial in North American and European populations and patients with non-metastatic and metastatic stage. Additionally, elevated NLR was related to worse OS in patients with melanoma, regardless of the sample size and the cut-off value.

Our findings suggest that elevated pretreatment NLR was associated with poor prognosis in melanoma patients, suggesting NLR might be a prognostic factor in patients with melanoma.

And again...

Neutrophil to lymphocyte ratio is an independent predictor of outcome for patients undergoing definitive resection for stage IV melanoma. Kanatsios, Melanoma Project, Li Wai Suen, et al. J Surg Oncol. 2018 Sep 9.

The aim of this study was to perform a retrospective analysis of survival rates and determine prognostic indicators for patients who underwent definitive surgical resection of stage IV melanoma.

Patients included were those who underwent complete resection of metastatic melanoma. Data was analyzed using IBM SPSS 2.0. Survival estimates were derived from Kaplan-Meier, log-rank, and Breslow tests.
The study population (n = 95) consisted of 60 males and 35 females. Median overall survival (OS) from the first metastasectomy was 49 months (31-67 months). OS at 1, 2, and 5 years was 92%, 87%, and 50% respectively. Predictors of survival included clear surgical margins compared to patients with positive margins (median OS 53 vs 20 months). A preoperative neutrophil to lymphocyte ratio less than 5 experienced a median OS of 65 months compared to 15 months.

This study's results are consistent with previous findings demonstrating favourable long-term outcomes following selective resection of metastatic melanoma. In addition to achieving clear surgical margins, a low preoperative neutrophil to lymphocyte ratio was associated with improved outcomes. These factors may help identify surgical candidates.  (As well as those who may need to more aggressively pursue systemic treatment - adjuvant or other wise. Just my 2 cents!!!)

For what it's worth.  Again. - c

Merry Christmas!!!

A jolly good time with my peeps, a few days ago....

Boys will be boys!!!

Testing things out in their own...

...special ways!

That's an excited baker right there!!!!

And here!

Visions of sugar plums are certainly dancing in her head!!!

Presents from Ruthie!!!

So much sweetness!!! Providing joy, a forward look, and the perfect talismans to make it so! 

And then ~ I won "SQUIRRELS"!!!!  Sho did!!  With the wrong rules....but still!!!  BAHAHAHAHA!!!

Thanks to all my peeps who cajole and encourage, pet and play, listen and make me laugh.  You're the best.  May you and your peeps have a Merry Christmas and a lovely holiday season!!! ~ love, les

Adjuvant BRAF/ MEK for Stage III melanoma patients along with some thoughts on adjuvant care from melanoma Big Dogs

As a follow-up to yesterday's post....here is a look at targeted therapy as adjuvant for melanoma.  Here's a link to several previous reports including an early report on the study below:  Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma.  Now, there's this:

Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected BRAF V600-Mutant Stage III Melanoma.

Hauschile, Dummer, Schadendorf, et al. J Clin Oncol. 2018 Oct 22.

Dabrafenib plus trametinib improved relapse-free survival (RFS) versus placebo in patients with resected BRAF V600-mutant stage III melanoma (BRF115532; COMBI-AD; ClinicalTrials.gov identifier: NCT01682083). We present an updated RFS analysis on the basis of extended study follow-up and a cure-rate model analysis to estimate the fraction of patients expected to remain relapse free long term.  In this phase III trial, patients with resected BRAF V600-mutant stage III melanoma were randomly assigned to 12 months of adjuvant dabrafenib plus trametinib versus placebo. We report updated RFS (primary end point) and distant metastasis-free survival. RFS was also analyzed by subgroups defined by baseline disease stage (American Joint Committee on Cancer 7th and 8th editions), nodal metastatic burden, and ulceration status. The fraction of patients who remained relapse free long term was estimated using a Weibull mixture cure-rate model.  At median follow-up of 44 months (dabrafenib plus trametinib) and 42 months (placebo), 3- and 4-year RFS rates were 59% and 54% in the dabrafenib plus trametinib arm and 40% and 38% in the placebo arm, respectively. Distant metastasis-free survival also favored dabrafenib plus trametinib. The estimated cure rate was 54% in the dabrafenib plus trametinib arm compared with 37% in the placebo arm. Subgroup analysis of RFS demonstrated similar treatment benefit regardless of baseline factors, including disease stage, nodal metastatic burden, and ulceration.  Longer follow-up confirmed RFS benefit with dabrafenib plus trametinib. Subgroup analysis suggested that dabrafenib plus trametinib benefited patients regardless of baseline factors.

And here are some thoughts on adjuvant treatment from the researchers themselves:

Adjuvant melanoma therapy with new drugs: should physicians continue to focus on metastatic disease or use it earlier in primary melanoma? Grob, Garbe, Ascierto, et al. Lancet Oncol. 2018 Dec.

It is important to differentiate between two concepts of adjuvant therapy in melanoma-what we have come to call late adjuvant and early adjuvant therapy. Early adjuvant therapy is defined as a medical intervention that is done after resection of a primary melanoma to eradicate possible undetectable minimal residual disease, whereas late adjuvant therapy is done when an overt metastatic disease (nodal or visceral) has been completely resected, to control disease better than if the same treatment were given at a later time, in the presence of multiple metastases. Early adjuvant therapy is thus a preventive treatment strategy, whereas late adjuvant therapy aims at anticipating treatment of metastatic disease. For patients with melanoma, 1-year treatment with targeted therapies and immunotherapy have only been assessed in late adjuvant settings, the outcomes of which more or less reproduce the same dramatic effect as they have in metastatic disease. However, early adjuvant therapy could provide greater benefits in terms of public health, since thin melanomas without nodal metastases are so common that they account for most deaths by melanoma. In the early adjuvant setting, a treatment course of less than 1 year might be sufficient to control the disease, with less toxicity and at reduced costs. In this Personal View, we discuss the potential benefit of short-term early adjuvant treatment in patients with stage II melanoma, with the hope that sentinel-node biopsy and the American Joint Committee on Cancer staging will soon be replaced by more relevant biomarkers to identify the most suitable candidates for early adjuvant therapy for this disease.

We've come a long way since the current immunotherapy and targeted treatments for melanoma were FDA approved in 2011.  We have much more to figure out in regard to adjuvant treatments.  And a long way to go in making sure that melanoma treatments are even more effective and accessible for ALL melanoma patients.  May 2019 bring more answers!!! - c

Neoadjuvant immunotherapy vs Adjuvant immunotherapy

Adjuvant therapy, is when a treatment is given AFTER signs of obvious disease have been removed, usually with surgery.  And we have very good data that adjuvant treatments, both with targeted and immunotherapy, work in melanoma to prevent progression in many of those patients.  After all, that is what the NED Stage IV ratties in my nivo trial proved from 2010 - 2013!!!!

NEO-adjuvant therapy, is when a treatment is given BEFORE melanoma has been removed.

Here are some prior posts - BRAF/MEK before surgery as well as after is MUCH better, than just AFTER surgery for melanoma!!

Now, there are these looking at immunotherapy as neoadjuvanat ~

Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma.  Amaria, Reddy, Tawbi, Davies, et al.  Nat Med. 2018 Oct 8.

Preclinical studies suggest that treatment with neoadjuvant immune checkpoint blockade is associated with enhanced survival and antigen-specific T cell responses compared with adjuvant treatment; however, optimal regimens have not been defined. Here we report results from a randomized phase 2 study of neoadjuvant nivolumab versus combined ipilimumab with nivolumab in 23 patients with high-risk resectable melanoma ( NCT02519322 ). RECIST overall response rates (ORR), pathologic complete response rates (pCR), treatment-related adverse events (trAEs) and immune correlates of response were assessed. Treatment with combined ipilimumab and nivolumab yielded high response rates (RECIST ORR 73%, pCR 45%) but substantial toxicity (73% grade 3 trAEs), whereas treatment with nivolumab monotherapy yielded modest responses (ORR 25%, pCR 25%) and low toxicity (8% grade 3 trAEs). Immune correlates of response were identified, demonstrating higher lymphoid infiltrates in responders to both therapies and a more clonal and diverse T cell infiltrate in responders to nivolumab monotherapy. These results describe the feasibility of neoadjuvant immune checkpoint blockade in melanoma and emphasize the need for additional studies to optimize treatment regimens and to validate putative biomarkers.

Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Blank, Rozeman, Fanchi, Sikorska, et al.  Nat Med. 2018 Oct 8.

Adjuvant ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) both improve relapse-free survival of stage III melanoma patients. In stage IV disease, the combination of ipilimumab + nivolumab is superior to ipilimumab alone and also appears to be more effective than nivolumab monotherapy. Preclinical work suggests that neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy. To address this question and to test feasibility, 20 patients with palpable stage III melanoma were 1:1 randomized to receive ipilimumab 3 mg kg and nivolumab 1 mg kg, as either four courses after surgery (adjuvant arm) or two courses before surgery and two courses postsurgery (neoadjuvant arm). Neoadjuvant therapy was feasible, with all patients undergoing surgery at the preplanned time point. However in both arms, 9/10 patients experienced one or more grade 3/4 adverse events. Pathological responses were achieved in 7/9 (78%) patients treated in the neoadjuvant arm. None of these patients have relapsed so far (median follow-up, 25.6 months). We found that neoadjuvant ipilimumab + nivolumab expand more tumor-resident T cell clones than adjuvant application. While neoadjuvant therapy appears promising, with the current regimen it induced high toxicity rates; therefore, it needs further investigation to preserve efficacy but reduce toxicity.

It is pretty clear that no matter how or when you take it, the ipi/nivo combo does much better than ipi or nivo alone.  It is also clear that the side effects will be greater.  Not news.  However, the real news is still out there.  Do melanoma peeps FAIL to progress more often when given treatment, in this case immunotherapy, BEFORE rendering them NED or giving them the treatment while some of their disease remains in place????  Inquiring minds NEED to KNOW!!!

Hang tough ratties.  You teach us all. - c

Reports on Intralesionals for melanoma - T-VEC, SD-101, and Dendritic cells

I have a few posts regarding melanoma that got put a bit on the back burner given the chaos that descended upon my world in August.  In the spirit of waste not, want not - thought I'd finish up the year with the last things that looked interesting in melanoma world ~

I still believe that intralesional therapies, especially when combined with a systemic therapy like Opdivo or Keytruda, are going to prove to be of great benefit to many melanoma patients!!!  Here are a zillion links to prior posts:  Intralesional/intratumoral therapy for Melanoma

Here are prior reports on T-VEC:  T-VEC (Talimogene Laherparepvec) for Melanoma  Now, there's this:

Talimogene Laherparepvec (TVEC) for the Treatment of Advanced Melanoma: A Single-Institution Experience.  Perez, Mirua, Naqvi, et al.  Ann Surg Oncol. 2018 Oct 8.   

Talimogene laherparepvec (TVEC) is an oncolytic herpes virus used as intralesional therapy for patients with unresectable stage IIIB through IV melanoma. We reviewed the standard of care treatment of TVEC at a single institution.  All patients treated with TVEC for advanced melanoma were retrospectively evaluated from 2015 to 2018. Patient demographics, clinicopathologic characteristics, treatment response, and toxicity were reviewed.  Twenty-seven patients underwent therapy with TVEC. Median age was 75 years, and 63% of patients were female. Seventeen (63.0%) patients underwent injections on the lower extremity, four (14.8%) on the upper extremity, four (14.8%) on the head and neck, and two (7.4%) on the trunk. Median number of injections was five. Median follow-up was 8.6 months. Of the 27 patients, 23 patients met the criteria for response analysis with at least 8 weeks follow-up. Ten (43.5%) patients experienced a complete response (CR), three (13.1%) experienced a partial response (PR), and five (21.7%) had stable disease (SD) for an overall response rate of 56.5% (CR + PR) and a disease control rate of 78.3% (CR + PR + SD). Adverse events were mostly limited to mild constitutional symptoms within 48 h of injection. Two patients developed cellulitis treated with oral antibiotics, and one patient underwent excision of a lesion for ulceration and bleeding during therapy. TVEC is an effective and well-tolerated intralesional therapy for patients with unresectable stage IIIB through IV melanoma. A CR was achieved in almost half of patients treated. Disease control is seen in the vast majority.  

SD-101 is another intralesional that is proving to have good results.  Here are prior reports:  SD - 101 in melanoma  Now, this summer, there was this:

SD-101 in Combination with Pembrolizumab in Advanced Melanoma: Results of a Phase Ib, Multicenter Study.  Ribas, Medina, Kummar, et al. Cancer Discov. 2018 Aug 28.

PD-1 inhibitors are approved for treating advanced melanoma, but resistance has been observed. This phase Ib trial evaluated intratumoral SD-101, a synthetic CpG oligonucleotide that stimulates Toll-like receptor 9 (TLR9), in combination with pembrolizumab in patients with unresectable or metastatic malignant melanoma. The most common adverse events related to SD-101 were injection-site reactions and transient, mild-to-moderate "flu-like" symptoms. Among the 9 patients naïve to anti-PD-1 therapy, the overall response rate (ORR) was 78%. The estimated 12-month progression-free survival rate was 88%, and the overall survival rate was 89%. Among 13 patients having prior anti-PD-1 therapy, the ORR was 15%. RNA profiling of tumor biopsies demonstrated increased CD8⁺ T cells, natural killer cells, cytotoxic cells, dendritic cells, and B cells. The combination of intratumoral SD-101 and pembrolizumab was well tolerated and induced broad immune activation in the tumor microenvironment with durable tumor responses in both peripheral and visceral lesions.

These early data demonstrate that the combination of pembrolizumab with intratumoral SD-101 is well tolerated and can induce immune activation at the tumor site. Combining an intratumoral TLR9 innate immune stimulant with PD-1 blockade can potentially increase clinical efficacy with minimal additional toxicity relative to PD-1 blockade alone.

Dendritic cells have been examined in many ways in melanoma care:  Dendritic cells in Melanoma  This study looks at them as an intralesional treatment combined with anti-PD-1 and radiation - in MICE:

Administration of dendritic cells and anti-PD-1 antibody converts X-ray irradiated tumors into effective in situ vaccines. Wang, Zenkoh, Gerelchulum, et al. Int J Radiat Oncol Biol Phys. 2018 Nov 17.  
Danger signals and release of tumor-specific antigens after exposure to ionizing radiation can convert an irradiated tumor into an in situ vaccine. However, radiation alone is not sufficient to induce an effective systemic immune response. In this study, we investigated whether a combination of X-ray irradiation with bone marrow-derived dendritic cell (BM-DC) and anti-PD-1 antibody (αPD1-ab) administration can enhance both local tumor control and the systemic abscopal effect in murine subcutaneous tumor models.

B16/BL6 melanoma and Lewis lung carcinoma (LLC) cells were examined of radiosensitivity and expression of H-2kb and PD-L1 before and after irradiation. The tumor cells were implanted subcutaneously in the left thigh of C57BL/6 mice as primary tumors. BM-DCs were induced from mouse bone marrow cells using GM-CSF and IL-4. The primary tumors were treated with 8 Gy of X-ray, followed by simultaneous intratumoral injection of BM-DCs and intraperitoneal injection of αPD1-ab. To examine the abscopal effect, the same tumor cells were also inoculated in the right thighs as metastatic tumors 4 days after the primary tumor inoculation, and only the primary tumors were treated with the same protocols. In vivo analyses of tumor growth and survival rates as well as in vitro analyses of splenic T-cell proliferation and interferon-γ (INF-γ) release were performed.  
The triple combination treatment of X-ray irradiation with BM-DC and αPD1-ab administration inhibited primary tumor growth and significantly extended the survival time in association with significant increase of T-cell proliferation and INF-γ release. In addition, this triple combination treatment significantly inhibited the growth of metastatic tumors.  The results indicated that BM-DC and αPD1-ab administration led to the conversion of irradiated tumors into effective in situ vaccines. This combination therapy can be a promising approach to develop a novel individualized therapy for patients with solid cancers.

Hang tough ratties!!! - c

Capecitibine smack down on Day #5!! "Ain't no skate'n with this $h*t!" ~ B

I was all set to write a jolly holiday post today after a really fun day with my critters yesterday!  It was splendid as I was feeling pretty well and their work/family schedules allowed them to visit at the same time.  It was great to get to be together to share a meal, talk and play!!!!  (Thanks, kiddos!!!  It was lovely and that post WILL happen!)

Over the past few days, the weird capecitibine rashes returned  ~ creating slightly itchy, but simultaneously tender, red papules to hands, palms, arms and face with dry, tan, cracked and peeling macules on my arms and legs.  Burning to palms and soles has been increasing intermittently.  But, I was still feeling rather cocky!  Four days into capecitbine I was only stooling 3-4 times a day.  Had one episode of cramping that was managed pretty well with Levsin.  But, at 0500 this morning, Capecitibine showed me who was boss with significant epigastric pain that rapidly spiraled into overall abdominal cramping with pain radiating to my back!  I tried tea and pepcid (which I've been taking daily for months) initially.  But, as the pain progressed B brought me levsin and marinol.  I've been resting a bit and it is a little better now.

I told B, "I thought I was going to skate through more easily this time."  Looking a bit grim, he replied, "Ain't  no skate'n with this $h*t!"  Adding, "You are again, dealing with colitis from the capecitibine."

Based on B's research and our conversations with my oncologist on how to manage this sort of thing, there will be no capecitibine for me today.  We'll see what happens tomorrow!!! - les

OH!!!  Marinol haze was about to make me forget!!  As most of you already know, I have also been dealing with residual Oxaliplatin created neuropathies that do seem to be improving gradually.  But, there is also this....

...a pic I took yesterday of my right arm.  The red streak is emanating from my last oxaliplatin infusion site.  Yes, oxaliplatin eats veins for breakfast.  Yes, it hurts like a booger.   Still not skate'n through that $h*t either!!!  But, I will!!  Someday!!!!!! - les

Sew Chaotically! ~ Foxy Shirt Dress - Simplicity 8014

In early spring, during a Jo Ann's shopping adventure, Roo picked this foxy flannel for the shirt dress of her dreams!  White with grey line drawings of foxes and tiny v-shaped checks of aqua! (I swear they are in there but could not for the life of me get the camera to pick them up!!!)  Her dream dress was spawned from this Simplicity shirt dress previously made here and here.  It is a great pattern that goes together very well.  BUT!  It is rather short and straight, making it a little too short on sitting if left as is.  Sew!!  I lengthened it a couple of inches and gently flared the skirt out a bit starting at the natural waist.  I think it worked!!!

She loved it!!!!!

Gotta say (again!!!) - Scott Boy Stoked about my pattern matching throughout!!  I've had so much fun making things to fit Roo's body, style and life!!!

Perhaps she shouldn't wear this particular dress when she visits her hen house!!  Love my girl!  - les

Capecitibine "WOKE" my Pollyanna A$$!

As planned, I started my first dose of my last round of capecitibine (say that five times fast!!) last night.  B offered/recommended that I take a marinol with it.  "Seriously," I objected, "how bad can the first dose be??  I'm heading to bed.  No thanks.  Don't need it."

Well, fast forward to 1 am this morning and I am WOKE!!  Alternating waves of feeling overheated and sweating versus shivering with cold wrenched me from sleep as the wall of nausea hit!!!   Poor B fetched the marinol, gave me a sweet back rub, and I faded back to sleep.  Feeling much better this morning, I shared this with a bestie, who you'd think would have my back, right?????

Hmmm.....

"Smh at u, how many times we gotta talk about listening to Brent!"

Bahahaha!!!  Yeah, she's still got my back although she is, literally, B's twin.  Same birthday, no joke!  My peeps are experts at keeping it real!  When they're right they're right.  This morning, I was good and took my marinol as directed. 

My day is sunny and bright, a bit warmer than expected.  My marinol hazy self trimmed my overgrown lavender (hope it grows back as my internet search said it would) and Knock Out Roses in preparation for spring. 

Hope springs eternal.  Thanks B and Tam Bo.  I will listen the first go round....next time.  I promise.  love, les

CAPOX - Final round, for ex-goblet cell adenocarcinoma of the appendix

At the oncologist's office bright and early this morning - feeling pretty well.  Less tired.  No significant stomach issues.  Fingers still numb.  Lots of numbness and weird sensations radiating up my arms.  Feet all jingy jangy with the clown shoe sensation back in place since last night.  So weird.  Anyhow, labs were okay.  WBC dropped back down to 4.3.  Hemoglobin pretty good at 12.5.  Met with the NP initially.  Shared the events of the past two weeks to which she promptly replied that it seemed to her additional oxaliplatin would be unwise; basing that recommendation on the same facts I reported yesterday.  1. This is a treatment that may not be doing much for me in the first place.  2.  The neuropathies I've been dealing with have a real chance of becoming permanent if we continue.  We assured her that we were of the same mind.  The oncologist joined us to complete the discussion. Conclusion?  No more oxaliplatin for me.  We agreed that I can probably tolerate the final 2 weeks of the oral medication (capecitibine), knowing that I can manipulate the dosage if side effects (diarrhea, cramping and weird skin dryness/rashes) become unmanageable.  Given the cessation of the oxaliplatin the remaining neuropathies should gradually resolve.  A recheck is  scheduled for January 7.

I'm okay with this.  It feels a bit weird to bail.  But, I don't want to put my ability to function -  as an NP, palpating little tummies and completing procedures as needed, as a sewist, cook, runner, and all the other things that require sensation of the hands and feet - in jeopardy if I can avoid it.  So, there you go.  I started my last 2 weeks of capecitibine just now.  Hopefully, it won't be too difficult.  Whatever it IS, it will soon be DONE and I will be soooooooooooooooooooo glad!!!

Thanks to all of you who have helped carry me through this decision making process.  - love, les

It's been rough, but CAPOX #3 = DONE!

Whew!  It's been rough around here since my oxaliplatin infusion on the 3rd, which due to my symptoms on the prior round had been pushed back a week, placing it in the middle of my two weeks of oral capecitibine.  Neuropathies, rather horrible diarrhea, and general miserableness have been in full swing.  B was a trooper and took great care of me.  Over the past 4 or 5 days things have improved as the oxaliplatin effects diminished and I began my week "off" the capecitibine.  I've been able to do a few chores about the house and even help B with a little yard work on a warmer day.  For the past couple of days I've also managed to complete my big 10 minutes on the elliptical!!  So there's that!

My dear ones have stepped up to comfort and entertain my limp self.  Don dropped by for a chat.  Kay was over bearing yummy lemon cookies for a good talk  and tea.  Friends sent encouraging texts and sweet notes.  And my Tam Bo made me laugh as only she can with this -

Who would have imagined that such things existed???  And Lord knows they were more than appropriate this round!!!  That girl will do anything to make me smile!  Thanks to all of you!!

The neuropathies were particularly intense this round despite the dose reduction and failing to complete the entire infusion.  I think I left that little factoid out when reporting my last ta dah.  Anyhow, the pain and nausea were so bad during the infusion, that when toward the end my IV infiltrated, the nurses declined to restart it and just called it a day.  I was too sick to argue and B was all for letting it go.  At any rate, even with that diminished dose, I developed what are considered Grade III neuropathies.  Instead of my fingers having the electric "jingy jangy" sensations only with cold, that feeling was produced whenever I touched anything - no matter how gently!  General body aches and burning to hands, arms and feet were worse than ever and were persistent until just a few days ago.  Now they are diminished and intermittent.  Then there was the fact that I couldn't make my hands tear toilet paper during the first 24 hours!  Even my lips have been doing weird numbness/tingling things which continues today.  It's been interesting to try to sew a little these past two days.  I'll pick up a pin to secure my seams, only to realize I have no pin!!!  I have had more problems with my feet than on prior infusions.  While is it getting better, I've felt as though I am walking in over sized clown shoes.  I asked B if I was walking weird and he said I didn't appear to be.  My reflexes (Yes - my Medical Meerkat checks those things though my doc has not!) have been fine.  Oh, well ~ I am mostly dealing with numbness in my fingers at this point.

With all that, I fear that I cannot tolerate the "final dose" of oxaliplatin I am scheduled for Monday.  We were advised during our consultation at Vanderbilt that permanent nerve damage is avoided by postponing the oxaliplatin dose and implementing a dose reduction for Grade II symptoms.  For Grade III neuropathies, which is what we feel I've experienced this time, cessation of the drug is indicated.  Additionally, given how ill I've been, I honestly don't know that I could will myself to embark on another round.  To admit that makes me feel like a wimp and a quitter, but I just don't think I can do it.  I know there are worse treatments out there.  I feel so very badly for folks who are enduring those!!!  But, given what I've experienced, the fact that I could have settled for no additional treatment other than the surgery, and the sad reality that we are not certain this adjuvant therapy is of any benefit to me - I don't think I can face more oxaliplatin.  I have an appointment for labs, a visit with the oncologist, and the last infusion first thing Monday morning, so we will discuss all of this with her then and see what she recommends.  I do feel that I can complete the final two weeks of oral capecitibine as planned. 

For the rest of the day, I will work on some secret sewing!!!

Super psyched about that pocket.  I know!  But...it's the little things!

Happy Sunday to you and yours! - les

SCARS are more than skin deep. The love that sees me through....

On the heels of yesterday's post, this morning I saw this amazing interview with Sarah Hyland that resonated perfectly with what I have been feeling ~

Sarah Hyland on Her Two Kidney Transplants | SELF

In part, she says, "Scars are scars.  They are little tally marks of what you've been through as a human being. ... When a family member gives you a second chance at life, and it fails, it almost feels like it's your fault.  And it's not.  But it does."

I feel so much of what she says intensely.  I am ashamed to have cancer ~ AGAIN!  I am so sorry for having put my family and dear ones through all this ~ AGAIN!!!  I am proud, and decidedly pissed, to have over 20 surgical scars and vitiligo.  It is hard to feel pretty when so much has been changed about you.  It is hard to feel strong when so much has been removed from your control.  It is hard to feel deserving of love from dear ones when so much suffering and work and sacrifice has been forced upon them - because of you and your weakness.

I have rambled on, and been inspired by many, when thinking about this over the years:

SCARS - More than skin deep

And yet, when checking my phone this morning - there was this:

"Good morning Wonder Woman. Sorry for the early text.  Heard this song and it made me think of you."   Lauren Daigle - Look Up Child

My dear TL!!!  Your text brought light and tears and love.  And I am thankful.

I don't know that this meandering missive really has a point other than honesty and the hope that love can provide.  I believe that shared truths make us stronger.  And the love and kindness that I am given daily, by so many, will see me through.

love, les

Sunshine in a Russian Novel

IF a Cancer Peep is extremely lucky, as death brings a rapid end for far too many, their life becomes something of a Russian novel.  There is pain and misery.  The landscape of endless doctor visits, scans, laboratories, and treatment rooms is cold and bleak.  Hours passed are long, tedious, and boring.  Dinners are bland.  Portions small and unappetizing.  Characters are unduly complicated, insisting upon actions that cause decidedly unpleasant side effects. Names are over long, difficult to pronounce, containing far too many consonants. The necessary narcissism of the protagonist negates their ability to participate in the lives of others, leading to isolation and a narrow, mean existence. Light, warmth, joy, color, and laughter are infrequent, distant, removed.  Sadness becomes pervasive.  Overall, life with cancer, or in a Russian novel, is a daunting effort - from the start.  Who among us has even begun War and Peace?  Much less finished it?  Twice?

As invalid invalids, [That first as: adjective - without validity; null; void.  The second as:  noun - sick person; made weak by illness or injury.]  Cancer Peeps suffer many casualties beyond their health.  Their job, their social circles, their identity.  The work to maintain a relationship with a Cancer Peep is just too hard, too distant, too complicated, too depressing, too great a mirror reflecting the uncontrolled nature of life and the certain conclusion of death, for many.  Abandonment by those believed to be bound to the Cancer Peep by love, loyalty, or even obligation, is one more shock in their already broken existence.

I have experienced those losses.  But, lucky bug that I am, I have been fortunate enough to walk that long, cold road, lined with dirty snow and debris blown by the harsh wind, the collar of my thin, worn coat turned up against it - TWICE!  The reality of being nothing to those you thought valued you highly, wounds in ways that can break your soul, but if survived and a bit of distance is afforded, you realize that those who would abandon you in your time of greatest need, were never there for you in the first place.  YOU were there for them.

It is easy to focus on such pain and abandonment.  Lord knows, lucky Cancer Peeps have plenty of time alone with their dismal thoughts.  Given the perverse nature of man, injustices and insults suffered tend to affect our spirit more than any acts of kindness and love if we are not careful.  To that end, I have worked to remember the reality of relationships that failed me, rather than the idea of them that I created.  I actively choose to prize the beauty of those dear ones who have remained loyal, true and kind through all my struggles and limited ability to participate in THEIR lives!  And I am blessed.  Blessed with dear ones near and far.  Blessed with those who see me.  Blessed by those who not only ask how I am, but then insist on listening to my litany of complaints, cheer me on and lift me up.  It is a rare gift.  Almost 4 months (or 15 years, depending on how you like to count) of misery in - my dear ones are not backing down.

Just this week, I received an entire package of sunshine. Apropos of nothing - and everything.

Fun, practical, useful, comforting - love - in the form of sunshine.

My dear sweet Connie.  13 years my mentor, leader and friend.  The kind of woman I hope to be when I grow up, knowing I never shall possess your unflappable grace, gentleness, or quiet strength.  Your example has meant more to me than you will ever know.  Your lovely yellow rays pierced my drab and dreary Russian novella.  Making me smile.  Making me believe in myself, and love, and spring.  Thank you, my friend. ~ celeste

Smack Down!! ~ CAPOX #3 and me

Tried to get this written yesterday, but it was not possible.  In fact, at one point as I was reading some of my correspondence, B said, "I hope you're not going to try to answer that just now," with clear concern that any response I might make would be less than cogent to say the least. We'll see how I do today~

As you may recall, my scheduled infusion of oxaliplatin for Monday a week ago, was postponed due to significant continued neuropathy and a white count of 3.9.  As reported Sunday, despite all that, I did restart the capecitibine as planned, added acetyl-L-carnitine, carried on with my exercise, and spent the week feeling pretty well.  When back to the office this past Monday, I figured this go round would come out decidedly better.  My neuropathies were much improved.  There were discreet points on my fingertips that still felt numb, but function was pretty much normal.  I attribute the improvement more to time, than anything else, but if the carnitine and exercise played a role - I'll take it.  I knew I was physically stronger than I have been during any of my other infusions.  I am certainly in a much better place nutritionally and have been maintaining a weight of 130 pounds.  I have been dealing with a great deal of redness and burning to my palms and soles, but the onc and I agreed that that was due to the capecitibine, not neuropathies related to the oxaliplatin.  My white count was only up to 4.1, but she was okay with that. My hgb was 12 and platelets 'good'.   With all that, we were a go.  So, with all my personal improvements, the oxaliplation at a 20% dose reduction and administered over 3 hours - this has to go better, right????

Had a good nurse, though Uninterested One, was still there, unkempt and smacking her gum as usual, while slumped in front of her computer.  Never spied a smile.  Good Nurse, got the IV started first stick with input welcomed from the patient.  We applied a heating pad from home at the start of the infusion.  But, as before, the infusion began burning before we got to the oxaliplatin.  The routine is a pre-dose of decadron, followed by aprepitant (a long acting anti-nausea medicine) then the oxaliplatin infusion.  This time I had the presence of mind to look it up and, yes!  Aprepitant itself can cause irritation to the veins.  So that answers that.  Happened to be seated next to Roo's second grade teacher receiving her final adjuvant chemo dose for recently diagnosed breast cancer. Ironically, just weeks ago when Roo was over for one of her fashion photo shoots, she mentioned this dear teacher, exclaiming, "Ms. M. saved my life!!!"  And indeed she had (and mine as well)!!! Within weeks of meeting Miss Rosie Roo, Ms. M. realized busy body Rose needed to busy her mind so as to stay out of trouble.  She promptly had her tested and placed in the school's gifted program.  Never thinking she would remember us, I still wanted this sweet, remarkable lady to know how much she had meant to Rose and our family.  But, before I could even begin, she recognized us at once, not only remembering Rose very clearly, with plenty of cute Roo stories, she shared that she has a 6 year old granddaughter who reminds her of Rose daily!!!  She was very pleased to hear Rose was teaching higher math, as her interest and ability in numbers, math, and puzzles were what had so impressed Ms. M. from the start.

Things faded fast after that exchange.  Though I had taken Marinol 5mg before leaving the house as we had done before, the nausea was worse than ever, necessitating two more doses during the infusion in order to barely manage it.  It was touch and go.  The neuropathies returned acutely, to a much greater degree than before, with incredible pain running from the infusion site up my entire arm.  Such that the lightest touch along my arm was excruciating.  After an arrival time of 0900, we made it home around 3:30.  Straight to bed with another dose of marinol and ativan.  With that I was out until 6:30 pm.  Woke up feeling kind of okay.  Managed to take a bit of broth from chicken noodle soup.  That went south quickly.  I tried resting my head on the table, but on trying to get to the bathroom, a mere 8 feet away, I fainted right in the floor.  Poor B!  We are both sure it was due to hypotension from all the meds combined with a vasovagal response with the nausea.  Managed to faint leaning against B in that bathroom.  We made it to the bathroom off the bedroom and repeated the process.  Finally made it to bed and slept through most of the night.

Yesterday, I barely remember.  Lots of drugs.  Nausea.  As before, I developed a really bad headache in the middle of the infusion.  I don't remember if I mentioned it previously, as I wasn't sure if it was related, but now I am.  It is a bit better today, as are the neuropathies, though they are still very significant, but something can brush against my right arm without throwing me into a fit!  We have tried to carry on with the scheduled capecitibine, though we did skip the dose Monday evening, and another this morning as I am dealing with cramping and diarrhea that I have now treated with immodium.  So, there you have it. My CAPOX smack down.

We will see how it goes.  B thinks it is unlikely that I can, or should, have any additional doses of oxaliplatin.  Only yesterday was I able to tear off a piece of toilet paper with my right hand.  That indicates a Grade III neuropathy even at the decreased dose.

Through all of this, I am vividly aware that there are those suffering through far more difficult regimens.  Plenty are having to endure FOLFOX and FOLFIRI - the STRONG version of CAPOX!!!  And there are a multitude of even more horrible tortures folks embark upon to try to save their lives.  While immunotherapy was not a walk in the park, and many ratties deal with more serious side effects from that treatment than I did, this chemo crap makes me miss it!!!

Thanks for the continued love and good wishes.  It takes a village.  I am blessed to have mine.  - c

CAPOX update - One week into Round 3 (oxaliplatin and capecitibine) as adjuvant for Ex-goblet cell adenocarcinoma of the appendix and an explanation of ~ Why the neuropthies, Man?????

As reported here, I did not get my scheduled oxaliplatin infusion Monday.  I did however, restart my oral capecitibine at 1 tab in the morning and two in the evening, after 3 tabs twice daily had caused stomach irritation to the point that I had to go down to 1 tab twice a day.  It has gone pretty well.  Some stomach cramping and large loose stools (4-5 per day) but certainly manageable compared to where I was.  My conjunctivitis has revved up again, though I am managing that with moisturizing drops.  Burning to palms has begun off and on, and the burning to the soles of my feet has become more persistent.  Skin stuff, the development of scattered red and brown spots, has continued though some of those that developed at the start have peeled off!  What the tub?

Anyhow, I've felt pretty well this week and since I wasn't knocked on my butt by the oxaliplatin I tried to make the most of it.  I've done research for spring planting.  Destruction of existing beds.  Salvaging plants.  The building of new beds.  What flowers to mix with veggies in a new "kitchen garden" I'm planning.  I've done a good bit of sewing and blogging.  Completing my TWO "sew frosting" challenges was so much fun with Roo.  I've researched fabric shopping in Atlanta.  Which may be a most agreeable first ta dah out of the box - that is my current condition!  A weekend trip we could make come spring!!!  B indulged me and we watched the BBC Sherlock mini series with Cumberbatch and Freeman for fun.  And, since I was feeling pretty good, I upped my exercise efforts.

I'll come back to that, but first, a little background.  When you consider neuropathies caused by CAPOX - here's the deal ~  There are two components to the condition when you are on this regimen.  Physiologically, nerves have several parts.  One is the nerve cell, the neuron.  Or if in a collection - ganglia.  These groups of neurons serve as our communication centers.  In the sensory nervous system, these nerves make up fibers that reach out into the surface tissues - the nerve endings that go to the surface of your body...like your fingertips, etc...and allow input from the skin to be registered as hot, cold, rough, smooth, pressure, pain, etc.  That sensation is transmitted back to the ganglia to connections via the spinal cord whose fibers then funnel this info to the brain.  The intel is then transmitted to the cortex of the brain and you go, "Whoa, this tea is hot!!!"  There is a complimentary motor system that sends messages to and from the muscle cells, but as it is not usually affected by CAPOX, we'll leave that be.  NOW ~ the neuropathy CAPOX causes is due to the oxaliplatin.  Oxaliplatin is made of two components - oxalate and a molecule containing platinum.  The neuropathy caused by oxaliplatin is unique in that it also has two parts related to its two constituents.  The oxalate makes the nerve fiber (the axon) dysfunction and stay in an excited state.  This is what causes the cold sensitivity - the extreme jingy jangy sensation that occurs when I touch or drink anything cold.  While unpleasant, it does not produce permanent damage and should gradually resolve on stopping treatment.  The platinum enters the neurons (the cell bodies in the ganglia) and causes damage to their mitochondria (structures within all cells that provide energy for cellular function)  which then causes the cell body to fail, malfunction, and produce the classic numbness and weird sensitivity that are paresthesias, also called neuropathies.  This process can lead to permanent injury and even death of the affected neuron causing loss of function of the nerve fibers that are connected to it.  Interestingly, this effect is directly correlated with the total amount of oxaliplatin given as well as the highest concentration in a given moment (the peak level of the medicine in the body) that the nerve cells are exposed to.  Therefore, if the dose is large, and/or given rapidly, the level of injury is greater.  Even a slowing of the administration can make a large dose more tolerable.  The neurons can recover, unless the cumulative damage or peak damage is too great.  Therefore, when folks are having neuropathies of Grade 2 or higher...the patient may need to delay additional doses, take the oxliplatin but at a reduced dose, and/or have the dose administered over a longer period of time.  If neuropathies do not improve with these interventions, then the patient may not be able to have any further doses of oxaliplatin at all.

Since the brain is FILLED with neurons, you might ask, "How do these neurons - basically the brain itself - avoid damage and death when you are given oxaliplatin?"  I have to thank heaven for my blood brain barrier!!!!  The BBB is a physical membrane that helps protect the brain from large molecules...in this instance...oxliplatin.  Now, if you have a brain tumor, the blood brain barrier can make getting appropriate treatment to the area difficult.  But, in my current condition, the BBB provides protection.  Thankfully, when I NEEDED treatment to a brain tumor, immunotherapy (the Opdivo I took for 2 1/2 years in my melanoma trial) served me very well!!  BECAUSE, when immunotherapy is given, it doesn't kill the melanoma on its own; unlike what we are hoping CAPOX is doing to any random adenocarcinoma cells I may have floating around!!!  Opdivo takes the brakes off the immune system that melanoma itself has placed upon it, while simultaneously triggering t cells the patient already has, to gear up and kill the melanoma they can now suddenly 'see' sitting right before them!   AND as I wrote a million times before local oncs could grasp this principle:  Yep! Immunotherapy can work in the brain...  But, back to the here and now...

Given those facts and my condition, my onc preferred to hold my oxaliplatin last week and recommended I start taking alpha lipoic acid, a nutritional supplement, as it could help resolve my neuropathies.  On the way home, my dutiful caretaker purchased a bottle for 20 bucks and I started it.  However, my Medical Meerkat, One Dwarf, and researcher in chief, could find no evidence whatsoever, that it did any good at all!  He did find some data that acetyl-L-carnitine, the stuff you get from eating a steak, could be beneficial.  After notifying my onc, and gaining her blessing, I am now taking that. It seems to me, based on Meerkat reporting, exercise has more benefit than anything else, so...like the good patient I am, if exercise works...I'll do that!!!  To that end, here's a text exchange I had with one of my besties ~ 

Me:  "I wore myself out yesterday and day prior.  B told me research showed that the only thing that REALLY helps neuropathies was exercise.  (The thing we got from the nutrition store per my onc has ZERO scientific proof of working...many papers...and yes, B sent them to the onc!!!) so B took me off it because, while it doesn't help the neuropathy, it does cause nausea.  Anyhow, I did 1.5 miles yesterday and the day prior on the elliptical and upped my sit-ups, push ups, etc.  Today...my body hurts!!!  Ha!  B said time for a day off.  When I told him why I did it...he just looked at me like I'm nutters and said...they mean take a walk...not kill yourself!!  😜"

Her response:  "Once again HE IS RIGHT!!   I'm SMH at u!"

Today we prepped for a very un-fun, one week va-cay.   It is not somewhere we want to go.  The scenery will be drab.  The food will suck.  Putrescence will prevail.  It will cost a fortune.  But, go we must, knowing the requirements of life (laundry, groceries, basic chores and ADL's) will not disappear just because!  So ~ today we prep.  Tomorrow we will see what happens.

Without failing to notice, there is beauty still....

Much love, c